Smallpox is considered one of the most dangerous potential biological weapons in existence because it is easily transmitted from person to person and no effective therapy exists. The overall mortality of smallpox infection is approximately 30% and patients who recover from this deadly illness frequently have disfiguring scars. Just as vaccination was the key to global eradication of smallpox 25 years ago, it would again be the key to any response to re-emergent smallpox. Along with its legacy of enormous success, the live virus smallpox vaccine has the dubious distinction of having one of the highest rates of vaccine-associated adverse events of any vaccine currently in routine use. The reluctance to give live smallpox vaccine widely is that the risk of serious complications in today's population may be significantly higher than 25 years ago. In particular, patients with atopic dermatitis (AD) are at high risk of developing eczema vaccinatum (EV), a serious potentially fatal side effect of smallpox vaccination that is associated with skin dissemination of vaccinia. The defects in host defense that results in EV are unknown nor are there any objective biomarkers available for identification of patients with AD who are at risk for development of EV and other viral infections such as eczema herpeticum. The current grant application is based on our recent finding that LL-37, an antimicrobial peptide that can be induced in keratincytes, kills vaccinia virus. We will test the hypothesis that the failure of AD keratinocytes to produce LL-37 and certain chemokines contributes to their susceptibility to EV. Specific aims will determine whether: 1) vaccinia virus-induces LL-37 expression in AD, but not psoriasis, skin is suppressed by Th2 cytokines (IL-4, IL-13); 2) chemokines deficient in AD, but not psoriasis, kill vaccinia virus; 3) there is any difference in expression of antimicrobial peptides and chemokines between skin biopsies from patients with extrinsic vs intrinsic AD. It is hoped that the proposed studies will elucidate the immunologic processes that result in EV, allow development of biomarkers that reliably identify patients at risk for this serious complication of smallpox vaccination and result in new strategies for treatment as well as prevention of EV.